# NM_000190.4(HMBS):c.992C>T (p.Ala331Val)

https://sugi.bio/variant/hmbs-p-ala331val

## Summary

**HMBS p.Ala331Val (c.992C>T)** is classified **Pathogenic/Likely pathogenic** in HMBS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-18). AlphaMissense: likely pathogenic (0.7842); Very rare (popmax 0.00267%, afr); Associated with acute intermittent porphyria.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs770086296 · 4 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the HMBS gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to acute intermittent porphyria.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult |
| Prevalence | <1 / 1 000 000 (Europe) |
| Clinical trials | 15 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | HMBS is a diagnostic-grade gene on 15 Genomics England panels |

**Commonly reported features of Acute intermittent porphyria** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abdominal pain — Very frequent (99-80%)
- Elevated urinary delta-aminolevulinic acid — Very frequent (99-80%)
- Porphyrinuria — Very frequent (99-80%)
- Increased urinary porphobilinogen — Very frequent (99-80%)
- Abnormal enzyme/coenzyme activity — Very frequent (99-80%)
- Renal insufficiency — Frequent (79-30%)
- Hypertension — Frequent (79-30%)
- Mental deterioration — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005732/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HMBS](https://sugi.bio/atlas/gene/HMBS/) |
| Protein change (HGVS p.) | p.Ala331Val |
| Coding change (HGVS c.) | c.992C>T |
| MANE Select transcript | [NM_000190](https://www.ncbi.nlm.nih.gov/nuccore/NM_000190) |
| dbSNP | [rs770086296](https://www.ncbi.nlm.nih.gov/snp/rs770086296/) |
| Variant type | single nucleotide variant |
| Location | chr11:119093189-119093189 (GRCh38) |
| ClinVar | [VCV851744](https://www.ncbi.nlm.nih.gov/clinvar/variation/851744/) |

**All HGVS expressions:** `LRG_1076:g.13313C>T`, `LRG_1076t1:c.992C>T`, `LRG_1076t2:c.941C>T`, `NC_000011.10:g.119093189C>T`, `NC_000011.9:g.118963899C>T`, `NG_008093.1:g.13313C>T`, `NM_000190.4:c.992C>T`, `NM_001024382.2:c.941C>T`, `NM_001258208.2:c.872C>T`, `NM_001258209.2:c.821C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.7842) — concordant with the pathogenic call
- REVEL 0.962 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -8.837 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 7.654, GERP 2.15, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.2**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.87** across the covering region of the MANE Select transcript (119,085,034–119,093,280), spanning 8,246 bp. Chi-square p 0.0046. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00267%** (afr) · FAF95 0.000688% · FAF99 0.000539% · 2/74,922 in the highest group · 19/1,614,060 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,240 |
| African / African-American (grpmax) | 0.00267% | 37,461 |
| Admixed American | 0.00167% | 60,006 |
| European (non-Finnish) | 0.00119% | 84,287 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**HMBS** population constraint: LOEUF 0.546, pLI 0.81406, missense-Z 1.3249; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **acute intermittent porphyria** — Definitive (SD)

## Protein context {#protein}

Residue **331** lies in a UniProt-annotated variant site (in aip); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 90.54, 79% of residues very-high.

**11 experimental structure(s)** (PDB): [3ECR](https://www.rcsb.org/structure/3ECR), [3EQ1](https://www.rcsb.org/structure/3EQ1), [5M6R](https://www.rcsb.org/structure/5M6R), [5M7F](https://www.rcsb.org/structure/5M7F), [7AAJ](https://www.rcsb.org/structure/7AAJ), [7AAK](https://www.rcsb.org/structure/7AAK) — incl. mutant structure 7AAK.

## What this gene does {#gene-function}

*Describes the biological roles of HMBS (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** HMBS's established molecular role includes hydroxymethylbilane synthase activity.


### Pathways affected {#pathways}

HMBS participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Heme biosynthesis](https://reactome.org/content/detail/R-HSA-189451) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** hydroxymethylbilane synthase activity.

**Biological process:** obsolete protoporphyrinogen IX biosynthetic process, heme biosynthetic process, heme B biosynthetic process.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-18.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic, 1 not provided).

**Submission history:** 4 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-01-20 |
| GenomeConnect - Invitae Patient Insights Network | not provided | no classification provided | phenotyping only |  |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-18 |

## Associated conditions {#conditions}

[acute intermittent porphyria](https://sugi.bio/atlas/disease/acute-intermittent-porphyria/).

**Reported phenotype names (ClinVar):** not provided, Acute intermittent porphyria, none provided, Acute Porphyria, PBGD DEFICIENCY, PORPHOBILINOGEN DEAMINASE DEFICIENCY, PORPHYRIA, SWEDISH TYPE, UPS DEFICIENCY, UROPORPHYRINOGEN SYNTHASE DEFICIENCY, HMBS deficiency.

## Similar variants {#similar}

Related HMBS variant pages (same residue, condition, or type): [HMBS p.Ala331=](/variant/hmbs-p-ala331), [HMBS c.160+5G>C](/variant/hmbs-c-160-plus-5g-c), [HMBS c.345-1G>A](/variant/hmbs-c-345-minus-1g-a), [HMBS c.613-1G>A](/variant/hmbs-c-613-minus-1g-a), [HMBS c.826-2A>T](/variant/hmbs-c-826-minus-2a-t), [HMBS c.913-1G>A](/variant/hmbs-c-913-minus-1g-a), [HMBS p.Arg116Trp](/variant/hmbs-p-arg116trp), [HMBS p.Arg149Ter](/variant/hmbs-p-arg149ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 851744). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*